Ovarian follicles are the basic units of female reproductive biology that contain a single oocyte (immature ovum or egg). These structures are periodically initiated to grow and develop, culminating in ovulation of usually a single oocyte in humans. These eggs/ova are developed only once every menstrual cycle (e.g. once a month in humans). A woman begins menstrual cycle at puberty with about 400,000 follicles. These dormant follicles are called primordial follicles. Once these follicles start growing they pass through different stages of follicular development; primary follicles, pre-antral follicles, antral and preovulatory follicles.
Anti-Müllerian hormone (AMH), also known as Müllerian inhibiting substance (MIS) or factor (MIF), has well defined roles in male sex differentiation. Across the female reproductive lifespan the role of AMH has, however, only more recently come to light. AMH is produced by granulosa cells (GCs) in small, growing ovarian follicles, and plays an important role in folliculogenesis. AMH acts as a natural follicular gatekeeper limiting follicle growth initiation and maintains the primordial follicle pool throughout the reproductive age. AMH is considered an intra-ovarian regulator that inhibits follicular atresia (death) at later stages of follicle development. Thus, if there is less AMH, then the initiation of primordial follicle growth becomes unchecked and follicles are lost faster than normal, resulting in a pathophysiological condition called diminished ovarian reserve (DOR) also known as premature ovarian aging (POA) and in some cases primary ovarian insufficiency (POI). Another common pathophysiological condition in women called polycystic ovary syndrome (PCOS) characterized by excessive follicle recruitment and arrest in the antral stage, resulting in impaired ovulation. These small follicles in PCOS produce high levels of AMH. AMH correlates to functional ovarian reserve, and is, therefore, used as a diagnostic and prognostic marker in infertility and in reproductive disorders like polycystic ovary syndrome (PCOS) (Fallet et al., 1997, Fertil Steril 67:962-5; Cook et al., 202, Fertil Steril 77:141-6; Pigny et al., 2003, J Clin Endocrinol Metab 88:5957-62) and POI (Visser et al., 2012, Nat Rev Endocrinol 8:331-41). It is also now routinely used to predict a ovarian response in in vitro fertilization (IVF) and other types of fertility treatment. Understanding AMH actions may, therefore, provide insights into follicular development under normal as well as pathophysiological conditions.
During folliculogenesis, AMH is expressed in GCs immediately following recruitment of follicles from the dormant primordial pool into the growing follicle pool, and continues to increase until follicles reach preantral and antral stages. Thereafter, AMH expression decreases and becomes undetectable during cyclic selection (Visser et al., 2012, Nat Rev Endocrinol 8:331-41). AMH expression is also absent in atretic follicles (Osman, 1985, J Reprod Fertil 73:261-70) and, notably, is considered an intra-ovarian inhibitor of follicular atresia (Visser et al., 2007, Endocrinology 148:2301-8).
AMH knockout (AMHKO) mouse model (Durlinger et al., 2002, Endocrinology 143:1076-84; Durlinger et al., 2001, Endocrinology 142:4891-9; Durlinger et al., 1999, 140:5789-96; Durlinger et al., 2002, Reproduction 124:601-9) provide major insights into AMH actions in folliculogenesis. AMH-deficient mice have significantly more growing follicles and develop POI. The AMH null mice demonstrated that ovarian AMH directly or indirectly prevents or inhibits primordial follicles from entering the pool of growing follicles. Interestingly, several previous in vitro studies in GCs (Durlinger et al., 2001, Endocrinology 142:4891-9; Durlinger et al., 2002, Reproduction 124:601-9; Kim et al., 1992, J Clin Endocrinol Metab 75:911-7; Chang et al., 2013, Fertil Steril 100:585-92 e581) have shown inhibitory effects of AMH on FSH-induced processes like proliferation, aromatase activity and luteinizing hormone receptor (LHR) expression across species (Clemente et al., 1994, Endocrine 2:553-8). Additionally, using an in vitro mouse follicle culture system, it also been reported that AMH inhibits FSH-stimulated follicle growth by decreasing the sensitivity of ovarian follicles to FSH (Durlinger et al., 2001, Endocrinology 142:4891-9; Visser and Themmen, 2014, Mol Cell Endocrinol 382:460-5). These in vivo and in vitro studies have established that, in addition to inhibiting the outgrowth of primordial follicles, AMH also inhibits FSH-stimulated follicle growth. Despite these studies and the wide utilization of AMH as a diagnostic and prognostic clinical marker, underlying mechanisms of AMH that regulate FSH actions and folliculogenesis, are still only poorly understood.
Thus, while the physiological regulatory role of AMH may be understood, there still a need in the art for compositions and methods utilizing AMH for treatment of women with impaired follicular development. The present invention satisfies this unmet need.